A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera

Abstract

Myeloproliferative disorders are clonal haematopoietic stem cell malignancies characterized by independency or hypersensitivity of haematopoietic progenitors to numerous cytokines. The molecular basis of most myeloproliferative disorders is unknown. On the basis of the model of chronic myeloid leukaemia, it is expected that a constitutive tyrosine kinase activity could be at the origin of these diseases. Polycythaemia vera is an acquired myeloproliferative disorder, characterized by the presence of polycythaemia diversely associated with thrombocytosis, leukocytosis and splenomegaly. Polycythaemia vera progenitors are hypersensitive to erythropoietin and other cytokines. Here, we describe a clonal and recurrent mutation in the JH2 pseudo-kinase domain of the Janus kinase 2 (JAK2) gene in most (> 80%) polycythaemia vera patients. The mutation, a valine-to-phenylalanine substitution at amino acid position 617, leads to constitutive tyrosine phosphorylation activity that promotes cytokine hypersensitivity and induces erythrocytosis in a mouse model. As this mutation is also found in other myeloproliferative disorders, this unique mutation will permit a new molecular classification of these disorders and novel therapeutical approaches.

JAK kinases overexpression promotes in vitro cell transformation

“…As a consequence, it is likely that progression to growth -factor independence after an isolated genetic event causing the overexpression of a JAK in a single cell in vivo would require that JAK-overexpressing cells have a selective advantage versus normal cells. Interestingly, as for JAK2 V617F and the response to EPO (James et al, 2005), we show that JAK overexpression increases the responsiveness to cytokines, at least for IL-9. So, in vivo, JAK overexpression could provide a growth advantage and favor the expansion of JAK-overexpressing cells in the presence of limiting cytokine concentrations.…”

“…Overexpression of JAKs is not sufficient to fully transform BaF3 cells, but a significant number of JAKoverexpressing cells can progress toward this stage, which can never be reached spontaneously by parental cells. This contrasts with the mutated JAK2 V617F, for which a majority of transfected BaF3 cells progress to cytokine-independent growth (James et al, 2005;Lu et al, 2005). In our system, autonomous transformation remains a rare event, which became detectable only when JAK-overexpressing cells were selected and expanded from the bulk parental Ba/F3 population.…”

“…The Tel-JAK2 fusion protein found in acute lymphoblastic leukemias (ALL) with the t(9;12) translocation leads to the constitutive activation of JAK2 and STAT5 (Lacronique et al, 1997). Recently, an activating mutation in JAK2 (V617F) was found in the majority of patients with polycythemia vera and a significant proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis (Baxter et al, 2005;James et al, 2005;Kralovics et al, 2005;Levine et al, 2005). When JAK2 V617F was transfected into factor-dependent cells, these cells became hypersensitive to cytokines and rapidly acquired cytokine independence, with constitutive activation of STAT5, the ERK/MAP kinase and the PI3/ AKT pathways.…”

MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients

“…The discovery of a somatic mutation (V617F) in the tyrosine kinase, Janus Kinase 2 (JAK2) [1][2][3][4][5], was the most important advance in MPN since the discoveries 30 years ago that hematopoiesis in these disorders was both autonomous and clonal [6][7][8]. Although the murine models have provided unequivocal evidence that JAK2 V617F is able to cause MPNs, there is significant heterogeneity in disease phenotypes between different murine lines and even within the same line, suggesting that disease phenotype is affected by other unknown genetic or epigenetic factors [2,[9][10][11][12]. In particular, PV is characterized by raised red cell mass and sometimes increased platelet and white cell counts, while ET is defined by an elevated platelet count alone and a normal red cell mass.…”

Kinase drug discovery approaches in chronic myeloproliferative disorders

“…In addition, TEL-PDGFRB and ZNF198-FGFR1 fusion genes have been identified as causal activation events in chronic myelomonocytic leukemia and 8p11 stem cell MPD, respectively (Golub et al, 1994;Carroll et al, 1996;Xiao et al, 1998;Chen et al, 2004). Most recently, several groups have identified gain-of-function mutations in Janus kinase 2 (JAK2) or thrombopoietin receptor (TPOR) in PV, ET and PMF, which lead to activation of JAK2 signaling, highlighting this kinase as an attractive therapeutic intervention point for these MPDs (Baxter et al, 2005;James et al, 2005;Kralovics et al, 2005;Levine et al, 2005;Tefferi et al, 2005). The discovery and successful therapeutic application of imatinib in both CML-and PDFR-rearranged eosinophilic MPD has provided a proof of concept for targeted therapy against these activated kinases in their associated malignancies (Druker et al, 2001;Sherbenou and Druker, 2007).…”